Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The baculovirus expression system has been used for the production of a variety of proteins, including antibodies. Two single-gene constructs encoding single-chain immunoglobulins have recently been developed. The antibody employed was monoclonal antibody (MAb) CC49 which reacts with the pancarcinoma antigen, tumor associated glycoprotein, TAG-72. One, single-chain construct designated SCA delta CLCH1 (SCIg), consists of the CC49 sFv covalently joined to the human Fc (gamma 1) through the hinge region. The other, SCA delta CLCH1-IL-2 (SCIg-IL-2), has a human IL-2 molecule attached to the carboxyl end of the SCIg. These constructs have been used to test the feasibility of producing biologically active antibodies using the baculovirus expression system. Both constructs have been successfully expressed in insect cells and purified. The baculovirus recombinant single-chain antibodies have been designated, bV-SCA delta CLCH1 (bV-SCIg) and bV-SCA delta CLCH1-IL-2 (bV-SCIg-IL-2) they have been shown to be secreted in the culture supernatant as dimeric molecules of approximately 115 kDa and 140 kDa, respectively. The specificity and antibody dependent cellular cytolytic activity of the baculovirus recombinant single-chain antibodies were shown to be similar to that of the myeloma derived molecules. Glycosylation analysis showed that baculovirus derived proteins were N-glycosylated, but carried few if any high mannose residues. The biological activity of the IL-2 moiety was retained in bV-SCIg-IL-2, as evidenced by its stimulatory effect on the proliferation of the IL-2 dependent cell line HT-2. The observation that a significantly shorter time is required to develop baculovirus recombinant molecules as compared to myeloma derived molecules and that insect cells express single chain MAbs at acceptable levels may have implications for the production of these molecules for clinical use.
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PMID:Baculovirus expression of a functional single-chain immunoglobulin and its IL-2 fusion protein. 759 24

A large expansion of activated T cells (CD3+CD25+) with the potential to act as anti-tumour effector cells is inducible in multiple myeloma (MM) patients by culturing bone marrow mononuclear cells (BMMCs) with the anti-CD3 monoclonal antibody (mAb) OKT3. The aim of this study was to provide a greater characterization of CD3-activated T cells. On day 6, most T cells coexpressed the CD11a, CD18, CD54, CD45R0 antigens and consisted of activated (CD25+) CD4+ and CD8+ cells in nearly equal proportions. Kinetics studies showed that CD4+CD25+ cells proliferated more rapidly and peaked earlier than CD8+CD25+ cells. When experiments were performed with purified subpopulations by removing CD4+ cells (resulting in CD8+ BMMCs) or by removing CD8+ cells (resulting in CD4+ BMMCs). T-cell activation and autologous plasma cell decrease were observed in CD4+ BMMCs only. Transwell cultures showed that CD4 help was necessary to make CD8+ BMMCs susceptible to CD3 stimulation. Relevant amounts of IL-2 were found in the supernatants of CD4+ BMMCs cultures, whereas no secretion of IL-4 was detected, indicating a Th1-like profile of CD3-activated CD4+ cells. These data indicate that CD4+ cells proliferate earlier and provide optimal help to induce the subsequent expansion of CD8+ cells after CD3 stimulation of MM BMMCs. Adequate stimulation of CD4+ cells is therefore essential in any strategy aiming to recover T-cell-mediated immunity in MM.
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PMID:CD3-induced T-cell activation in the bone marrow of myeloma patients: major role of CD4+ cells. 764 4

After treatment with human normal IgM, 78 +/- 8% of purified CD3-CD56+ resting human NK cells and 93 +/- 6% of IL-2-activated NK cells selected by adherence to plastic reacted with FITC-goat anti-human IgM. Binding of IgM to the FcR for IgM (Fc mu R) on human NK cells was not species specific because mouse myeloma IgM also bound to these cells. The percentage of CD56+ cells binding IgM after incubation with anti-CD16 mAb was similar to that of cells incubated with medium alone (95 +/- 1% vs 93 +/- 4%). Binding of anti-CD16 mAb to Fc gamma RIII on NK cells was unaffected by pretreatment with IgM (65 +/- 12% vs 69 +/- 4%). The CD7 molecule has been reported to be the Fc mu R on the surface of T cells. Two-color flow cytometry showed that 94 +/- 3% of CD3-CD56+ resting NK cells and 71 +/- 16% of activated NK cells were CD7+. Preincubation of NK cells with three anti-CD7 mAb (Leu-9, 8H8-1, and LAU-A1) failed to block the binding of IgM to the Fc mu R. Modulation of the CD7 molecule off the cell surface (CD7+ = 1.5% +/- 0.3) did not reduce IgM binding, thus excluding the possibility that IgM anti-CD7 might bind to different epitopes of the same molecule. These data indicate that the Fc mu R is a specific Ig-binding structure, distinct from the Fc gamma RIII (CD16) or CD7. The Fc mu R on NK cells functions as a signal-transducing molecule because the addition of 0.2 mg/ml IgM to R-NK cells caused a rapid increase in [Ca2+]i (delta = 40 nM). One of the early events that followed signaling through the Fc mu R was the down-modulation of IFN-gamma gene expression and IFN gamma production in NK cells. The presence of IgM during culture of NK cells consistently decreased the expression of HLA-DR (16% vs 40% in control). Thus, the Fc mu R, a constitutively-expressed receptor on human NK cells, seems to be an important functional molecule, which delivers negative regulatory signals to NK cells.
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PMID:Characterization of the Fc mu receptor on human natural killer cells. Interaction with its physiologic ligand, human normal IgM, specificity of binding, and functional effects. 769 Jul 92

A number of environmental cells in the bone marrow (BM) of multiple myeloma (MM) has been reported to be activated. Evidence is growing that many cytokines, namely IL-6, IL-1 beta, TNF and GM-CSF, are detected in the BM of MM. Tumor environment may support, not only MM cell proliferation, but also bone resorption. In addition, immuno-regulatory cells, both CD8+T cells and NK cells, are also activated. High serum IL-2 levels are indicated. Recently, we detected numerous CD5+NK cells, which may be activated, in the peripheral blood and the BM of MM.
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PMID:[Myeloma cells and cytokines]. 769 93

Idiotype-specific T cells were characterized in patients with multiple myeloma stage I by analysing idiotype-induced DNA synthesis (3H-thymidine incorporation), IL-2 and IFN-gamma production at the single cell level (ELISPOT) (in vitro tests) and delayed type hypersensitivity (DTH) skin reaction (in vivo test). In seven out of eight patients at least one of the four tests was positive. In five patients three or more tests were positive. One patient was negative in all four tests. Six patients had both IL-2 and IFN-gamma-secreting cells and three of them also a DTH response. Furthermore, those three patients with a proliferative response also had IL-2 and IFN-gamma-secreting cells induced by the idiotype. The data indicate that part of the idiotype-specific T cell fraction belongs to the CD4 Th1 cell population. Whether CD8-specific T cells also were present could not be ruled out. The present study provides further support for the existence of idiotype-specific T cells in multiple myeloma. Such cells might be an important target for an immune-mediated therapeutic approach.
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PMID:Idiotype-specific T cells in multiple myeloma stage I: an evaluation by four different functional tests. 783 49

In vitro data have demonstrated autologous T-lymphocytes with anti-tumour activity in multiple myeloma (MM). Therefore a phase I/II trial was conducted to study the feasibility, the effect on several immunological parameters, and the tumour response induction of low-dose recombinant interleukin-2 (rIL-2) in MM patients. 18 MM patients of advanced stages in progress, who had failed on standard chemotherapy received 9 x 10(6) IU/m2 rIL-2 twice daily on days 1 and 2 and 0.9 x 10(6) IU/m2 twice daily for 5 subsequent days per week subcutaneously from days 3 to 56 (repeated every 12 weeks until progression). Patients were treated for between 8 and 1086 + d (mean 241 d) without serious side-effects. 6/17 patients experienced tumour response (2/17 objective tumour mass reduction, 4/17 long-lasting stable disease following tumour progression before initiation of rIL-2 treatment). During therapy the number of eosinophils increased 15-fold, CD4+ T lymphocytes were activated as demonstrated by enhanced CD25 antigen expression, and CD56+ NK cells expanded in the peripheral blood. Furthermore, a diminished pre-treatment ratio of CD4+/CD8+ lymphocytes was normalized during rIL-2 treatment. NK cell activity and lymphokine activated killer (LAK) cell activity was significantly enhanced. Endogenous IL-2 production and elevated soluble IL-2 receptor serum concentrations were induced. Low-dose rIL-2 can stimulate immune enhancement in MM despite the characteristic tumour-induced immunodeficiency. The treatment has proven though limited efficacy in advanced MM. Because most of the responders experienced termination of tumour progression rather than tumour regression, rIL-2 maintenance of chemotherapy-induced remissions should be investigated.
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PMID:Low-dose recombinant interleukin-2 therapy in advanced multiple myeloma. 787 83

Prognostic factors in myeloma are not only important for allowing comparisons to be made between therapeutic protocols but they also provide us with an insight into the pathophysiology of the disease and important mechanisms which result in disease progression. Prognostic factors in myeloma relate to the inherent proliferative capacity of the malignant clone, tumor bulk, renal function and other factors which reflect tumor host and host tumor interactions. The highly significant effect of the labelling index (LI) suggests that the clonogenic cell is ontologically very close to the malignant plasma cell on which the labelling index is derived. The explanation for the important role of the beta 2-microglobulin (beta 2M) level over and above its reflection of renal function is as yet unclear. Other factors involved in prognosis such as serum cytokines (IL-2 and IL-6) and soluble IL-6 receptor levels reflect host tumor interactions. An understanding of these interactions may allow us to control the disease and prevent escape from plateau phase by biological means. This may become a viable alternative to high dose aggressive chemotherapy which up till now appears unable to eradicate the malignant clone.
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PMID:Prognostic factors in myeloma: what they tell us about the pathophysiology of the disease. 787 94

The authors review contemporary findings on the role of different components of the cytokine network from the aspect of development, prognosis and treatment of multiple myeloma. Greatest attention was devoted to the main growth factor of myeloma elements IL-6, but also to the real or so far sparsely elucidated role of other cytokines (IL-1, IL-2, GM-CSF, G-CSF, IL-3, IL-4, IL-5, IL-10, TNF, interferon alpha and gamma) under conditions in vitro and in vivo. For completeness sake the authors did not omit the problem of the soluble receptor of IL-2 and the role of TNF, TNF beta and in particular IL-1 beta in the pathogenesis of osteolytic lesions and the potential therapeutic role of antibodies against IL-6 (anti IL-6 mab) and interferon alpha and gamma.
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PMID:[The cytokine network in multiple myeloma]. 794 39

Follicular dendritic cells (FDC) are specialized cells residing primarily within lymphoid follicles. They bind immunocomplexes and play an important role in the presentation of antigen to follicular B cells. Isolation of FDC for in vitro studies, however, is difficult because they constitute only about 1% of the cells in lymphoid tissue and form tight clusters entrapping lymphocytes within their dendritic processes. The monoclonal antibody (mAb) Ki-M4, which is highly restricted in its binding to FDC, is used to identify these cells. In order to establish a new immortalized cell line with features of FDC, we applied a modified procedure to isolate and enrich FDC from human tonsils and fused them with the myeloma cell line SP2/0-Ag14. The new hybrid cell line, designated FDC-H1, is of both mouse lymphoid and human FDC origin. FDC-H1 was found to have unlimited growth potential and to consistently express the Ki-M4 antigen and other surface antigens of human FDC. Semiquantitative reverse-transcribed polymerase chain reaction (RT-PCR) of enriched FDC and FDC-H1 revealed the same highly restricted cytokine/mRNA profile for both, with detectable levels of interleukin (IL)-1 alpha and surface CD23 and a lack of mRNA for IL-1 beta, IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, interferon-gamma, tumor necrosis factor-alpha, transforming growth factor-beta and granulocyte/macrophage-colony-stimulating factor. Additionally a weak but constant IL-6 mRNA expression was found in the cell line FDC-H1 by RT-PCR. In situ hybridization experiments in tonsils revealed IL-6 transcripts in cells with a staining pattern characteristic of a dendritic cell only in a few germinal centers. To our knowledge, FDC-H1 is the first cell line that constantly expresses surface antigens and a cytokine profile characteristic of FDC. It is, therefore, well suited for studying the biology of FDC and the functional relationship between FDC and normal or neoplastic lymphatic cells.
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PMID:An immortalized cell line with features of human follicular dendritic cells. Antigen and cytokine expression analysis. 795 61

To further the study of natural killer (NK) cells we have produced hamster monoclonal antibodies (MAbs) with reactivities to mouse NK cells. MAbs 4A2 and 3C2 were obtained by fusing spleen cells from Syrian hamsters immunized with IL-2-activated NK cells with Fox-NY myeloma cells. 4A2 antigen was expressed by bone marrow (BM)-derived IL-2-responsive NK cell precursors, by mature NK cells of the BM, and by a highly lytic subset of splenic NK cells, in addition to IL-2-activated NK cells. 3C2 antigen was also expressed by BM-derived NK cell precursors, by mature NK cells in the BM, at low levels by splenic NK cells, and at high levels by IL-2-activated NK cells. These MAbs are likely to provide useful reagents for the study of the life history and functional significance of NK cells.
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PMID:Hamster monoclonal antibodies to murine natural killer cells. 811 Nov 93


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